U.S. patent application number 16/090072 was filed with the patent office on 2019-05-09 for novel pyrimidine-4-carboxylic acid derivative having anticancer activity.
The applicant listed for this patent is INDUSTRY-UNIVERSITY COOPERATION FOUNDATION HANYANG UNIVERSITY, KOREA INSTITUTE OF SCIENCE AND TECHNOLOGY. Invention is credited to HanNa CHO, Seung Hye CHOI, Woo Young HUR, Gu KONG, Jeong Yeon LEE, Byeong Yun LIM, In Jae SHUN, Tae Bo SIM, Chi Man SONG, Ho Jong YOON.
Application Number | 20190135765 16/090072 |
Document ID | / |
Family ID | 58581257 |
Filed Date | 2019-05-09 |
View All Diagrams
United States Patent
Application |
20190135765 |
Kind Code |
A1 |
SIM; Tae Bo ; et
al. |
May 9, 2019 |
NOVEL PYRIMIDINE-4-CARBOXYLIC ACID DERIVATIVE HAVING ANTICANCER
ACTIVITY
Abstract
The present invention relates to a novel pyrimidine-4-carboxylic
acid derivative having an anticancer activity, and the compound of
the present invention is useful as a drug for treating and
preventing tumor diseases.
Inventors: |
SIM; Tae Bo; (Seoul, KR)
; HUR; Woo Young; (Seoul, KR) ; YOON; Ho Jong;
(Seoul, KR) ; SONG; Chi Man; (Seoul, KR) ;
SHUN; In Jae; (Seoul, KR) ; LIM; Byeong Yun;
(Seoul, KR) ; CHO; HanNa; (Seoul, KR) ;
CHOI; Seung Hye; (Seoul, KR) ; KONG; Gu;
(Seoul, KR) ; LEE; Jeong Yeon; (Seoul,
KR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
KOREA INSTITUTE OF SCIENCE AND TECHNOLOGY
INDUSTRY-UNIVERSITY COOPERATION FOUNDATION HANYANG
UNIVERSITY |
Seoul
Seoul |
|
KR
KR |
|
|
Family ID: |
58581257 |
Appl. No.: |
16/090072 |
Filed: |
March 30, 2017 |
PCT Filed: |
March 30, 2017 |
PCT NO: |
PCT/KR2017/003463 |
371 Date: |
September 28, 2018 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 35/00 20180101;
A61K 31/505 20130101; C07D 409/12 20130101; C07D 405/12 20130101;
C07D 403/12 20130101; C07D 239/42 20130101; A61K 31/506
20130101 |
International
Class: |
C07D 239/42 20060101
C07D239/42; A61P 35/00 20060101 A61P035/00; C07D 405/12 20060101
C07D405/12; C07D 409/12 20060101 C07D409/12; C07D 403/12 20060101
C07D403/12 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 30, 2016 |
KR |
10-2016-0038606 |
Claims
1. A compound selected from the group consisting of a
pyrimidine-4-carboxylic acid compound represented by the following
Formula 1, a hydrate thereof, solvate thereof, isomer thereof,
racemate thereof and pharmaceutically acceptable salt thereof:
##STR00025## wherein Q is a C.sub.6-C.sub.15 aryl group; or a
C.sub.4-C.sub.13 heteroaryl group substituted with 1-3
heteroatom(s) selected from the group consisting of N, O and S; R
is a halogen atom; a C.sub.1-C.sub.10 haloalkyl group substituted
with 1-13 halogen atom(s); a C.sub.1-C.sub.10 alkoxy group; a 5- or
6-membered heterocycloalkyl group substituted with 1-2
heteroatom(s) selected from the group consisting of N and O; or
--(CH.sub.2).sub.r--R.sup.1; R.sup.1 is a hydrogen atom; a
C.sub.1-C.sub.10 alkoxy group; an amino group; a
mono(C.sub.1-C.sub.10 alkyl)amino group; a di(C.sub.1-C.sub.10
alkyl)amino group; or --NHC(O)--C.sub.6H5; n and r are an integer
of 0 to 6; and m is an integer of 0 to 3.
2. The compound according to claim 1, wherein Q is an aryl group
selected from the group consisting of phenyl, biphenyl and
naphthalenyl; or a heteroaryl group selected from the group
consisting of furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl,
pyridinyl, pyrimidinyl, pyridazinyl and indazolyl; R is a halogen
atom selected from the group consisting of chlorine, fluorine,
bromine and iodine; a trifluoromethyl group; an alkoxy group
selected from the group consisting of methoxy, ethoxy,
normal-propoxy, iso-propoxy and tert-butoxy; a heterocycloalkyl
group selected from the group consisting of morpholino,
piperidinyl, piperazinyl and N--(C.sub.1-C.sub.10
alkyl)piperazinyl; or --(CH.sub.2).sub.r--R, wherein R.sup.1 is a
hydrogen atom, a methoxy group, an ethoxy group, a propoxy group,
an amino group, a methylamino group, a dimethylamino group, a
diethylamino group or a benzamido group; n and r are an integer of
0 to 6; and m is an integer of 0 to 3.
3. The compound according to claim 1, wherein Q is a phenyl group,
a biphenyl group, a naphthalenyl group, a furanyl group, a
thiophenyl group, a pyrazolyl group, a pyridazinyl group or an
indazolyl group; R is chlorine, fluorine, a trifluoromethyl group,
a methoxy group, a 4-ethylpiperazin-1-yl group, a methyl group, an
ethyl group, a propyl group, a 2-(dimethylamino)ethyl group, a
3-(dimethylamino)propyl group or a 3-(benzamido)propyl group; n is
0 or 1; and m is 0, 1 or 2, wherein a compound, wherein Q is a
phenyl group, a biphenyl group or a naphthalenyl group, R is
chlorine or fluorine, n is 0, and m is 1 or 2, is excluded.
4. The compound according to claim 1, wherein the
pyrimidine-4-carboxylic acid compound represented by Formula 1 is
selected from the group consisting of:
5-(([1,1'-biphenyl]-4-ylmethyl)amino)pyrimidine-4-carboxylic acid;
5-((2,4-dimethoxybenzyl)amino)pyrimidine-4-carboxylic acid;
5-((3,4-dichlorobenzyl)amino)pyrimidine-4-carboxylic acid;
5-((furan-2-ylmethyl)amino)pyrimidine-4-carboxylic acid;
5-(((3-methylthiophen-2-yl)methyl)amino)pyrimidine-4-carboxylic
acid; 5-((4-fluorobenzyl)amino)pyrimidine-4-carboxylic acid;
5-((3,5-bis(trifluoromethyl)benzyl)amino)pyrimidine-4-carboxylic
acid; 5-((4-methoxybenzyl)amino)pyrimidine-4-carboxylic acid;
5-((4-methylbenzyl)amino)pyrimidine-4-carboxylic acid;
5-((3-fluorobenzyl)amino)pyrimidine-4-carboxylic acid;
5-((2-fluorobenzyl)amino)pyrimidine-4-carboxylic acid;
5-((1-propyl-1H-indazol-3-yl)amino)pyrimidine-4-carboxylic acid;
5-((1-(2-(dimethylamino)ethyl)-1H-indazol-3-yl)amino)pyrimidine-4-carboxy-
lic acid;
5-((1-(3-benzamidopropyl)-1H-pyrazol-4-yl)amino)pyrimidine-4-car-
boxylic acid;
5-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidine-4-carboxylic acid;
5-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine-4-carboxylic acid;
5-(pyridazin-3-ylamino)pyrimidine-4-carboxylic acid;
5-(naphthalen-1-ylamino)pyrimidine-4-carboxylic acid;
5-((1-(3-(dimethylamino)propyl)-1H-pyrazol-4-yl)amino)pyrimidine-4-carbox-
ylic acid; and
5-((4-(4-ethylpiperazin-1-yl)phenyl)amino)pyrimidine-4-carboxylic
acid.
5. A pharmaceutical composition for treating and preventing a tumor
disease comprising, as an active ingredient, a compound selected
from the group consisting of a pyrimidine-4-carboxylic acid
compound represented by the following Formula 1, a hydrate thereof,
solvate thereof, isomer thereof, racemate thereof and
pharmaceutically acceptable salt thereof: ##STR00026## wherein Q is
a C.sub.6-C.sub.15 aryl group; or a C.sub.4-C.sub.13 heteroaryl
group substituted with 1-3 heteroatom(s) selected from the group
consisting of N, O and S; R is a halogen atom; a C.sub.1-C.sub.10
haloalkyl group substituted with 1-13 halogen atom(s); a
C.sub.1-C.sub.10 alkoxy group; a 5- or 6-membered heterocycloalkyl
group substituted with 1-2 heteroatom(s) selected from the group
consisting of N and O; or --(CH.sub.2).sub.r--R.sup.1; R.sup.1 is a
hydrogen atom; a C.sub.1-C.sub.10 alkoxy group; an amino group; a
mono(C.sub.1-C.sub.10alkyl)amino group; a di(C.sub.1-C.sub.10
alkyl)amino group; or --NHC(O)--C.sub.6H5; n and r are an integer
of 0 to 6; and m is an integer of 0 to 3.
6. The pharmaceutical composition according to claim 5, wherein Q
is an aryl group selected from the group consisting of phenyl,
biphenyl and naphthalenyl; or a heteroaryl group selected from the
group consisting of furanyl, thiophenyl, pyrazolyl, oxazolyl,
isoxazolyl, pyridinyl, pyrimidinyl, pyridazinyl and indazolyl; R is
a halogen atom selected from the group consisting of chlorine,
fluorine, bromine and iodine; a trifluoromethyl group; an alkoxy
group selected from the group consisting of methoxy, ethoxy,
normal-propoxy, iso-propoxy and tert-butoxy; a heterocycloalkyl
group selected from the group consisting of morpholino,
piperidinyl, piperazinyl and N--(C.sub.1-C.sub.10
alkyl)piperazinyl; or --(CH.sub.2).sub.r--R, wherein R.sup.1 is a
hydrogen atom, a methoxy group, an ethoxy group, a propoxy group,
an amino group, a methylamino group, a dimethylamino group, a
diethylamino group or a benzamido group; n and r are an integer of
0 to 6; and m is an integer of 0 to 3.
7. The pharmaceutical composition according to claim 5, wherein Q
is a phenyl group, a biphenyl group, a naphthalenyl group, a
furanyl group, a thiophenyl group, a pyrazolyl group, a pyridazinyl
group or an indazolyl group; R is chlorine, fluorine, a
trifluoromethyl group, a methoxy group, a 4-ethylpiperazin-1-yl
group, a methyl group, an ethyl group, a propyl group, a
2-(dimethylamino)ethyl group, a 3-(dimethylamino)propyl group or a
3-(benzamido)propyl group; n is 0 or 1; and m is 0, 1 or 2.
8. The pharmaceutical composition according to claim 5, wherein the
pyrimidine-4-carboxylic acid compound represented by Formula 1 is
selected from the group consisting of:
5-(([1,1'-biphenyl]-4-ylmethyl)amino)pyrimidine-4-carboxylic acid;
5-((2,4-dimethoxybenzyl)amino)pyrimidine-4-carboxylic acid;
5-((3,4-dichlorobenzyl)amino)pyrimidine-4-carboxylic acid;
5-((furan-2-ylmethyl)amino)pyrimidine-4-carboxylic acid;
5-(((3-methylthiophen-2-yl)methyl)amino)pyrimidine-4-carboxylic
acid; 5-((4-fluorobenzyl)amino)pyrimidine-4-carboxylic acid;
5-((3,5-bis(trifluoromethyl)benzyl)amino)pyrimidine-4-carboxylic
acid; 5-((4-methoxybenzyl)amino)pyrimidine-4-carboxylic acid;
5-((4-methylbenzyl)amino)pyrimidine-4-carboxylic acid;
5-((3-fluorobenzyl)amino)pyrimidine-4-carboxylic acid;
5-((2-fluorobenzyl)amino)pyrimidine-4-carboxylic acid;
5-((1-propyl-1H-indazol-3-yl)amino)pyrimidine-4-carboxylic acid;
5-((1-(2-(dimethylamino)ethyl)-1H-indazol-3-yl)amino)pyrimidine-4-carboxy-
lic acid;
5-((1-(3-benzamidopropyl)-1H-pyrazol-4-yl)amino)pyrimidine-4-car-
boxylic acid;
5-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidine-4-carboxylic acid;
5-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine-4-carboxylic acid;
5-(pyridazin-3-ylamino)pyrimidine-4-carboxylic acid;
5-(naphthalen-1-ylamino)pyrimidine-4-carboxylic acid;
5-((1-(3-(dimethylamino)propyl)-1H-pyrazol-4-yl)amino)pyrimidine-4-carbox-
ylic acid; and
5-((4-(4-ethylpiperazin-1-yl)phenyl)amino)pyrimidine-4-carboxylic
acid.
9. A theoretical agent for a tumor disease comprising, as an active
ingredient, a compound selected from the group consisting of a
pyrimidine-4-carboxylic acid compound represented by the following
Formula 1, a hydrate thereof, solvate thereof, isomer thereof,
racemate thereof and pharmaceutically acceptable salt thereof:
##STR00027## wherein Q is a C.sub.6-C.sub.15 aryl group; or a
C.sub.4-C.sub.13 heteroaryl group substituted with 1-3
heteroatom(s) selected from the group consisting of N, O and S; R
is a halogen atom; a C.sub.1-C.sub.10 haloalkyl group substituted
with 1-13 halogen atom(s); a C.sub.1-C.sub.10 alkoxy group; a 5- or
6-membered heterocycloalkyl group substituted with 1-2
heteroatom(s) selected from the group consisting of N and O; or
--(CH.sub.2).sub.r--R.sup.1; R.sup.1 is a hydrogen atom; a
C.sub.1-C.sub.10 alkoxy group; an amino group; a
mono(C.sub.1-C.sub.00alkyl)amino group; a di(C.sub.1-C.sub.10
alkyl)amino group; or --NHC(O)--C.sub.6H5; n and r are an integer
of 0 to 6; and m is an integer of 0 to 3.
10. The theoretical agent according to claim 9, wherein the tumor
disease is selected from the group consisting of prostate cancer,
breast cancer, bladder cancer, lung cancer, and melanoma.
Description
TECHNICAL FIELD
[0001] The present invention relates to a novel
pyrimidine-4-carboxylic acid derivative having histone demethylase
inhibitor activity.
BACKGROUND ART
[0002] Gene expression regulation occurs not only by direct
chemical methylation change of DNA, but also by methylation of
histone proteins linked to nucleosomes which are structures in
which DNAs are highly condensed. Among enzymes relating to such
epigenetic inheritance, histone demethylases attract much attention
as promising anti-cancer drug targets.
[0003] Enzymes for selectively demethylating methyl groups linked
to histone lysine may be broadly classified into the LSD class and
the JmjC class. The LSD class is an amineoxidase using FAD as a
co-factor, which is involved in demethylation of mono- and
di-methyl lysine of H3K4. The JmjC class is an dioxygenase that has
a Jumonji C (JmjC) domain and uses Fe (II) and alpha-ketoglutaric
acid as co-factors, which is involved in demethylation of mono-,
di- or tri-methyl lysine. Somatic mutation of histone demethylase
was almost not found, but it was reported to be overexpressed in
some carcinomas, which induces development of cancer. For example,
RBP2 is an enzyme that demethylates di- and/or tri-methylation
groups of histone H3 lysine 4 (H3K4me2/3), which facilitates
expression of various genes (for example, TNC) relating to
metastasis and serves as an essential epigenetic switch determining
cancer metastasis. In addition, RBP2 is over-expressed in lung
cancer tissue, genetic knockdown of RBP2 inhibits growth, movement,
permeation and metastasis of lung cancer cells. Since research
results demonstrating that, in lung cancer cell lines, RBP2
facilitates expression of cyclin D1 and E1, and expression of
integrin-.beta.1 associated with metastasis, were reported,
inhibitory mechanisms of histone demethylase including RBP2 have
attracted a great deal of attention as promising targets for novel
anti-cancer drugs.
[0004] Meanwhile, WO 2014/100818 discloses that a novel
pyrimidine-4-carboxylic acid derivative represented by the
following Formula A has inhibitory activity against histone
demethylase, and is useful for the treatment of tumor diseases such
as prostate cancer, breast cancer, bladder cancer, lung cancer,
and/or melanoma and the like.
##STR00001##
[0005] However, it has not been reported to date that the compound
having a pyrimidine-4-carboxylic acid core structure suggested by
the present invention has histone demethylase inhibitor
activity.
DISCLOSURE
Technical Problem
[0006] Thus, it is one object of the present invention to provide a
novel compound having a core structure of pyrimidine-4-carboxylic
acid.
[0007] Also, it is another object of the present invention to
provide a pharmaceutical use of the novel compound as a drug for
treating or preventing tumor diseases, based on inhibitory activity
of the compound against histone demethylase.
Technical Solution
[0008] In order to accomplish the objects described above, in one
aspect, the present invention provides a pyrimidine-4-carboxylic
acid compound represented by the following Formula 1, a hydrate
thereof, solvate thereof, isomer thereof, racemate thereof or
pharmaceutically acceptable salt thereof:
##STR00002##
[0009] wherein
[0010] Q is a C.sub.6-C.sub.15 aryl group; or a C.sub.4-C.sub.13
heteroaryl group substituted with 1-3 heteroatom(s) selected from
the group consisting of N, O and S;
[0011] R is a halogen atom; a C.sub.1-C.sub.10 haloalkyl group
substituted with 1-13 halogen atom(s); a C.sub.1-C.sub.10 alkoxy
group; a 5- or 6-membered heterocycloalkyl group substituted with
1-2 heteroatom(s) selected from the group consisting of N and O; or
--(CH.sub.2).sub.r--R.sup.1;
[0012] R.sup.1 is a hydrogen atom; a C.sub.1-C.sub.10 alkoxy group;
an amino group; a mono(C.sub.1-C.sub.10 alkyl)amino group; a
di(C.sub.1-C.sub.10 alkyl)amino group; or --NHC(O)--C.sub.6H5;
[0013] n and r are an integer of 0 to 6; and
[0014] m is an integer of 0 to 3.
[0015] In another aspect, the present invention provides a
theoretical or prophylactic agent for a tumor disease containing,
as an active ingredient, a compound selected from the group
consisting of the pyrimidine-4-carboxylic acid compound represented
by Formula 1, a hydrate thereof, solvate thereof, isomer thereof,
racemate thereof and pharmaceutically acceptable salt thereof.
Advantageous Effects
[0016] The pyrimidine-4-carboxylic acid compound according to the
present invention is highly capable of inhibiting histone
demethylase such as KDM5A. Accordingly, the pyrimidine-4-carboxylic
acid compound of the present invention can be used as an active
ingredient of a pharmaceutical composition for treating or
preventing a tumor disease such as prostate cancer, breast cancer,
bladder cancer, lung cancer, and melanoma.
BEST MODE
[0017] The present invention relates to a pyrimidine-4-carboxylic
acid compound represented by the following Formula 1:
##STR00003##
[0018] wherein
[0019] Q is a C.sub.6-C.sub.15 aryl group; or a C.sub.4-C.sub.13
heteroaryl group substituted with 1-3 heteroatom(s) selected from
the group consisting of N, O and S;
[0020] R is a halogen atom; a C.sub.1-C.sub.10 haloalkyl group
substituted with 1-13 halogen atom(s); a C.sub.1-C.sub.10 alkoxy
group; a 5- or 6-membered heterocycloalkyl group substituted with
1-2 heteroatom(s) selected from the group consisting of N and O; or
--(CH.sub.2).sub.r--R.sup.1;
[0021] R.sup.1 is a hydrogen atom; a C.sub.1-C.sub.10 alkoxy group;
an amino group; a mono(C.sub.1-C.sub.10alkyl)amino group; a
di(C.sub.1-C.sub.10 alkyl)amino group; or --NHC(O)--C.sub.6H5;
[0022] n and r are an integer of 0 to 6; and
[0023] m is an integer of 0 to 3.
[0024] The compound represented by the following Formula 1
according to the he present invention may have one or more chiral
centers and, in the case of such a compound, an enantiomer or
diastereomer may be present. Accordingly, the present invention
includes respective isomer compounds, and a mixture or racemate of
these isomers.
[0025] In addition, the present invention includes a radioactive
derivative in which a radioactive element is introduced into the
compound represented by Formula 1 and the radioactive compound is
useful for the biotherapy field through imaging.
[0026] In addition, a pharmaceutically acceptable salt can be
produced from the compound represented by Formula 1 according to
the present invention by an ordinary method well-known in the art.
For example, non-toxic inorganic acids such as hydrochloric acid,
bromic acid, sulfonic acid, amidosulfuric acid, phosphoric acid and
nitric acid, or non-toxic organic acids such as propionic acid,
succinic acid, glycolic acid, stearic acid, lactic acid, tartaric
acid, citric acid, para-toluenesulfonic acid and methane-sulfonic
acid, and pharmaceutically acceptable salts of these salts can be
formed.
[0027] In addition, a part of the compound represented by Formula 1
according to the present invention can be crystallized or
re-crystallized from a solvent such as aqueous and organic
solvents. In this case, a solvate can be formed. Not only compounds
containing a variety of amounts of water that can be produced by a
method such as lyophilization, but also hydrates and stoichiometric
solvates fall into the scope of the present invention.
[0028] Substituents used to define the compound represented by
Formula 1 according to the present invention will be described in
more detail.
[0029] As used herein, the terms "halo" and "halogen atom", which
mean chlorine, fluorine, bromine or iodine, can be used
interchangeably.
[0030] As used herein, the term "alkyl" means a linear, branched or
cyclic aliphatic saturated hydrocarbon group having 1 to 10 carbon
atom(s), preferably 1 to 6 carbon atom(s), more preferably 1 to 4
carbon atom(s). Specifically, examples of the alkyl group include a
methyl group, an ethyl group, a normal-propyl group, an iso-propyl
group, a cyclopropyl group, a cyclopropylmethyl group, a
normal-butyl group, an iso-butyl group, a tert-butyl group, a
cyclobutyl group, a normal-pentyl group, an iso-pentyl group, a
neopentyl group, a tert-pentyl group, a cyclopentyl group, a
normal-hexyl group, an iso-hexyl group, a cyclohexyl group, a
normal-heptyl group, a normal-octyl group and the like.
[0031] As used herein, the term "alkoxy" means an alkyl group of
carbon linked to oxygen wherein the alkyl is defined as above.
[0032] As used herein, the term "haloalkyl" includes all linear and
branched carbon chains that include 1 to 13 halogen atom(s) such as
fluorine, chlorine, bromine and iodine, and have 1 to 10 carbon
atom(s). Preferred haloalkyl groups include a fluoromethyl group, a
trifluoromethyl group, a 1,2-dichloroethyl group, a
1,1-dichloroethyl group, a pentafluoroethyl group and the like.
[0033] As used herein, the term "heterocycloalkyl" means a five- or
six-membered, saturated or partially saturated aliphatic cyclic
group that includes 1 to 2 heteroatom(s) selected from the group
consisting of 0 and N. Specifically, examples of the
heterocycloalkyl group include a tetrahydrofuranyl group, a
2,3-dihydrofuranyl group, a 2,5-dihydrofuranyl group, a
pyrrolidinyl group, a 2,3-dihydropyrrolidinyl group, a
2,5-dihydropyrrolidinyl group, a tetrahydro-2H-pyranyl group, a
3,4-dihydro-2H-pyranyl group, a 4H-pyranyl group, a piperidinyl
group, a 1,2,3,4-tetrahydropyridinyl group, a 1,4-dihydropyridinyl
group, a piperazinyl group, an N-protected piperazinyl group, a
morpholino group and the like. The N-protective group of
piperazinyl may typically include a C.sub.1-C.sub.10 alkyl
group.
[0034] As used herein, the term "aryl" means a mono-, di- or
tri-cyclic aromatic hydrocarbon group having 6 to 15 carbon atoms.
Specifically, examples of the aryl group include a phenyl group, a
biphenyl group, a naphthalenyl group, an anthracenyl group, a
phenanthrenyl group and the like.
[0035] As used herein, the term "heteroaryl" means a mono-, di- or
tri-cyclic aromatic group that includes 1 to 3 heteroatom(s)
selected from the group consisting of N, O and S, and has 4 to 13
carbon atoms. Examples of the heteroaryl include a pyrrolyl group,
a pyrazolyl group, an imidazolyl group, a furanyl group, an
oxazolyl group, an isoxazolyl group, a thiophenyl group, a
thiazolyl group, an isothiazolyl group, a pyridinyl group, a
pyrazinyl group, a pyridazinyl group, a pyrimidinyl group, an
indolyl group, an isoindolyl group, an indazolyl group, a
benzimidazolyl group, a benzothiazolyl group, a benzisothiazolyl
group, a quinolinyl group, an isoquinolinyl group, a phthalazinyl
group, a quinazolinyl group and the like.
[0036] The compound represented by Formula 1 is preferably a
compound,
[0037] wherein Q is an aryl group selected from the group
consisting of phenyl, biphenyl and naphthalenyl; or a heteroaryl
group selected from the group consisting of furanyl, thiophenyl,
pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl,
pyridazinyl and indazolyl,
[0038] R is a halogen atom selected from the group consisting of
chlorine, fluorine, bromine and iodine; a trifluoromethyl group; an
alkoxy group selected from the group consisting of methoxy, ethoxy,
normal-propoxy, iso-propoxy and tert-butoxy; a heterocycloalkyl
group selected from the group consisting of morpholino,
piperidinyl, piperazinyl and N--(C.sub.1-C.sub.10
alkyl)piperazinyl; or --(CH.sub.2)r-R, wherein R.sup.1 is a
hydrogen atom, a methoxy group, an ethoxy group, a propoxy group,
an amino group, a methylamino group, a dimethylamino group, a
diethylamino group or a benzamido group,
[0039] n and r are an integer of 0 to 6, and
[0040] m is an integer of 0 to 3.
[0041] The compound represented by Formula 1 is more preferably a
compound,
[0042] wherein Q is a phenyl group, a biphenyl group, a
naphthalenyl group, a furanyl group, a thiophenyl group, a
pyrazolyl group, a pyridazinyl group or an indazolyl group,
[0043] R is chlorine, fluorine, a trifluoromethyl group, a methoxy
group, a 4-ethylpiperazin-1-yl group, a methyl group, an ethyl
group, a propyl group, a 2-(dimethylamino)ethyl group, a
3-(dimethylamino)propyl group or a 3-(benzamido)propyl group,
[0044] N is 0 or 1, and
[0045] M is 0, 1 or 2.
[0046] Specifically, examples of the pyrimidine-4-carboxylic acid
compound represented by Formula 1 according to the present
invention are given below: [0047]
5-(([1,1'-biphenyl]-4-ylmethyl)amino)pyrimidine-4-carboxylic acid;
[0048] 5-((2,4-dimethoxybenzyl)amino)pyrimidine-4-carboxylic acid;
[0049] 5-((3,4-dichlorobenzyl)amino)pyrimidine-4-carboxylic acid;
[0050] 5-((furan-2-ylmethyl)amino)pyrimidine-4-carboxylic acid;
[0051]
5-(((3-methylthiophen-2-yl)methyl)amino)pyrimidine-4-carboxylic
acid; [0052] 5-((4-fluorobenzyl)amino)pyrimidine-4-carboxylic acid;
[0053]
5-((3,5-bis(trifluoromethyl)benzyl)amino)pyrimidine-4-carboxylic
acid; [0054] 5-((4-methoxybenzyl)amino)pyrimidine-4-carboxylic
acid; [0055] 5-((4-methylbenzyl)amino)pyrimidine-4-carboxylic acid;
[0056] 5-((3-fluorobenzyl)amino)pyrimidine-4-carboxylic acid;
[0057] 5-((2-fluorobenzyl)amino)pyrimidine-4-carboxylic acid;
[0058] 5-((1-propyl-1H-indazol-3-yl)amino)pyrimidine-4-carboxylic
acid; [0059]
5-((1-(2-(dimethylamino)ethyl)-1H-indazol-3-yl)amino)pyrimidine-4-carboxy-
lic acid; [0060]
5-((1-(3-benzamidopropyl)-1H-pyrazol-4-yl)amino)pyrimidine-4-carboxylic
acid; [0061]
5-((l-methyl-1H-pyrazol-3-yl)amino)pyrimidine-4-carboxylic acid;
[0062] 5-((l-methyl-1H-pyrazol-4-yl)amino)pyrimidine-4-carboxylic
acid; [0063] 5-(pyridazin-3-ylamino)pyrimidine-4-carboxylic acid;
[0064] 5-(naphthalen-1-ylamino)pyrimidine-4-carboxylic acid; [0065]
5-((1-(3-(dimethylamino)propyl)-1H-pyrazol-4-yl)amino)pyrimidine-4-carbox-
ylic acid; and [0066]
5-((4-(4-ethylpiperazin-1-yl)phenyl)amino)pyrimidine-4-carboxylic
acid.
[0067] Meanwhile, the present invention includes a pharmaceutical
composition containing, as an active ingredient, the compound
represented by the following Formula 1, a hydrate thereof, solvate
thereof, isomer thereof, racemate thereof or pharmaceutically
acceptable salt thereof.
[0068] The compound represented by Formula 1 exhibits excellent
inhibitory activity against histone demethylase and can thus be
used as a drug for preventing or treating tumor diseases induced by
abnormal cell growth.
[0069] The protein histone demethylase may, for example, include
KDM4A, KDM5A, KDM5B, KDM6B, LSD1 and the like.
[0070] Examples of the tumor diseases induced by abnormal cell
growth according to the present invention include a variety of
cancer diseases such as prostate cancer, breast cancer, bladder
cancer, lung cancer, melanoma and the like.
[0071] The pharmaceutical composition of the present invention can
be prepared into a formulation ordinarily used in the
pharmaceutical field, for example, a formulation for oral
administration such as a tablet, a capsule, a troche, a
liquid/solution, a suspension or the like, or a formulation for
parenteral administration, by incorporating, as an active
ingredient, the compound represented by Formula 1, a hydrate
thereof, solvate thereof, isomer thereof, racemate thereof or
pharmaceutically acceptable salt thereof, and further adding an
ordinary non-toxic pharmaceutically acceptable carrier, adjuvant,
excipient or the like thereto.
[0072] The excipient that can be used for the pharmaceutical
composition of the present invention includes a sweetener, a
binder, a solubilizer, a solubilizing aid, a wetting agent, an
emulsifier, an isotonic agent, an adsorbent, a disintegrant, an
antioxidant, a preservative, a lubricant, a filler, a fragrance or
the like. Examples of the excipient include lactose, dextrose,
sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc,
stearic acid, stearin, magnesium stearate, magnesium aluminum
silicate, starch, gelatin, tragacanth gum, alginic acid, sodium
alginate, methyl cellulose, sodium carboxymethyl cellulose, agar,
water, ethanol, polyethylene glycol, polyvinyl pyrrolidone, sodium
chloride, calcium chloride, orange essence, strawberry essence,
vanilla fragrance and the like.
[0073] In addition, the dosage of the compound according to the
present invention applied to human may be determined depending on
age, body weight, administration routes, health conditions and
disease severity of patients. The dosage is generally 0.01 to 1,000
mg/day on the basis of an adult patient with a body weight of 70 kg
and the compound may be administered at one time or multiple times
(portionwise) daily at a predetermined interval according to
prescriptions of physicians or pharmacists.
[0074] Meanwhile, the present invention provides a method for
preparing the compound represented by Formula 1.
[0075] The compound represented by Formula 1 according to the
present invention can be prepared by a preparation method including
a series of steps in accordance with the following Reaction Scheme
1:
##STR00004##
[0076] wherein Q, R, n and m are each defined as in Formula 1.
[0077] In accordance with Reaction Scheme 1 above, the compound
represented by Formula 1 can be prepared by the preparation method
according to the present invention including two steps using, as a
starting material, bromine-substituted ethyl
pyrimidine-4-carboxylate represented by Formula 2 above.
[0078] The first step includes reacting the bromine-substituted
ethyl pyrimidine-4-carboxylate represented by Formula 2 with an
appropriate amine compound represented by Formula 3 above in the
presence of a base, a palladium catalyst and xantphos, to prepare
an amine-substituted ethyl pyrimidine-4-carboxylate represented by
Formula 4 above.
[0079] In this case, the base may be an inorganic base selected
from the group consisting of hydroxides, oxides, carbonates,
sulfates and the like of alkali metals or alkaline earth metals,
and is preferably a carbonate of an alkali metal or alkaline earth
metal such as calcium carbonate. A representative example of a
useful palladium catalyst is tris(dibenzylideneacetone)dipalladium
(0) (Pd.sub.2dba.sub.3). The reaction is preferably performed at a
temperature of 70.degree. C. to 150.degree. C., more preferably at
a reflux temperature of the solvent. The reaction solvent may be an
ordinary organic solvent. Toluene, which is a representative
example of an aromatic hydrocarbon, is used in the example of the
present invention, but the solvent of present invention is not
limited thereto.
[0080] The second step includes hydrolyzing the amine-substituted
ethyl pyrimidine-4-carboxylate represented by Formula 4, to prepare
the pyrimidine-4-carboxylic acid compound represented by Formula
1.
[0081] The hydrolysis may be carried out under acidic or basic
conditions, preferably under basic conditions. A useful hydrolase
may include an alkali metal hydroxide such as lithium hydroxide or
sodium hydroxide. A hydrolysis temperature is about room
temperature and is specifically maintained at a temperature of
20.degree. C. to 30.degree. C. A hydrolysis solvent may be a
combined solvent of water and an organic polar solvent. In this
case, the organic polar solvent may include one or more selected
from the group consisting of C.sub.1 to C.sub.4 alcohol,
tetrahydrofuran (THF), dimethylformamide (DMF), dimethylsulfoxide
(DMSO) and the like.
[0082] The aforementioned present invention will be described in
more detail with reference to the following Example. The following
Example and Test Example are provided only for illustration of the
present invention and should not be construed as limiting the scope
of the present invention.
Example
Example 1: Synthesis of
5-(([1,1'-biphenyl]-4-ylmethyl)amino)pyrimidine-4-carboxylic
acid
##STR00005##
[0084] Step 1: [1,1'-biphenyl]-4-carbaldehyde oxime
[0085] NH.sub.2OH.HCl (757 mg, 11.0 mmol) and Na.sub.2CO.sub.3 (873
mg, 8.23 mmol) were dissolved in water (4 mL), and the resulting
solution was slowly added dropwise to a solution of
[1,1'-biphenyl]-4-carbaldehyde (1,000 mg, 5.48 mmol) in ethanol (10
mL), followed by stirring at 105.degree. C. for 30 minutes. After
completion of the reaction, the reaction solution was allowed to
cool to room temperature and was distilled under reduced pressure
to remove 1/3 of the solvent, and the residue was diluted with
water and extracted using ethyl acetate. The collected organic
layer was dried over anhydrous magnesium sulfate and filtered, and
the solution was concentrated under reduced pressure to obtain the
titled compound as a white solid (1047.3 mg, 97% yield).
[0086] .sup.1H NMR (400 MHz, CHCl.sub.3) .delta. 8.03 (s, 1H),
7.76-7.75 (m, 1H), 7.65-7.62 (m, 3H), 7.57-7.56 (m, 1H), 7.45-7.42
(m, 3H), 7.35-7.31 (m, 1H).
Step 2: [1,1'-biphenyl]-4-ylmethanamine
[0087] [1,1'-biphenyl]-4-carbaldehyde oxime (1,000 mg, 5.48 mmol)
was dissolved in methanol (20 mL), and NaBH.sub.4 (976.0 mg, 25.8
mmol) and NiCl.sub.2.6H.sub.2O (1022.1 mg, 4.3 mmol) were slowly
added dropwise to the resulting solution, followed by stirring at
room temperature for 30 minutes. After completion of the reaction,
the reaction solution was diluted with a 1% NH.sub.4OH solution and
extracted using ethyl acetate. The collected organic layer was
dried over anhydrous magnesium sulfate and filtered, and the
solution was concentrated under reduced pressure. The obtained
residue was purified by column chromatography
(DCM:MeOH:NH.sub.4OH=80:19:1) to obtain the titled compound as a
yellow oil (2.59 g, 82% yield).
[0088] .sup.1H NMR (400 MHz, CHCl.sub.3) .delta. 7.61-7.53 (m, 4H),
7.44-7.30 (m, 5H), 3.87 (2H, s), 1.53 (br s, 2H).
Step 3: Ethyl
5-(([1,1'-biphenyl]-4-ylmethyl)amino)pyrimidine-4-carboxylate
[0089] Ethyl 5-bromopyrimidine-4-carboxylate (35.0 mg, 0.15 mmol),
[1,1'-biphenyl]-4-ylmethanamine (30.0 mg, 0.18 mmol),
K.sub.2CO.sub.3 (62 mg, 0.45 mmol) and toluene (1 mL) were charged
in a sealed tube and the tube was then degassed. Xantphos (27 mg,
0.045 mmol) and Pd.sub.2(dba).sub.3 (14 mg, 0.015 mmol) were added
to the reaction solution, followed by stirring at 110.degree. C.
for 3 hours. After completion of the reaction, the reaction
solution was allowed to cool to room temperature and filtered
through a Celite pad using ethyl acetate. The filtrate was
concentrated under reduced pressure and the obtained residue was
purified by column chromatography (silica,
MPLC:EtOAc:n-Hexane=20:80 to 50:50) to obtain the titled compound
as a pale yellow solid (39.5 mg, 79% yield).
[0090] LC-MS m/z [M+H].sup.+=334
Step 4:
5-(([1,1'-biphenyl]-4-ylmethyl)amino)pyrimidine-4-carboxylic
acid
[0091] Ethyl
5-(([1,1'-biphenyl]-4-ylmethyl)amino)pyrimidine-4-carboxylate (39.5
mg, 0.12 mmol) and LiCl (7.6 mg, 0.18 mmol) were added to a mix
solution of methanol (1 mL), THF (1 mL) and H.sub.2O (1 mL),
followed by stirring at room temperature for 30 minutes. After
completion of the reaction, the reaction solution was acidified
with an aqueous 1N HCl solution. The acidized solution was
extracted using a mix solution of chloroform/isopropanol (4:1). The
collected organic layer was dried over anhydrous magnesium sulfate
and filtered, and the solution was concentrated under reduced
pressure to obtain the titled compound as a pale yellow solid (34.8
mg, 97%).
[0092] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.48 (s, 1H),
8.01 (br s, 1H), 7.65-7.63 (m, 4H), 7.46-7.42 (m, 4H), 7.34 (t,
J=8.0 Hz, 1H), 4.64 (s, 2H)
Example 2. Synthesis of
5-((2,4-dimethoxybenzyl)amino)pyrimidine-4-carboxylic acid
##STR00006##
[0094] The titled compound was synthesized with reference to the
method illustrated in Example 1, except that an appropriate amine
was used instead of [1,1'-biphenyl]-4-ylmethanamine in step 2 of
Example 1.
[0095] LC-MS m/z [M+H].sup.+=290.
Example 3. Synthesis of
5-((3,4-dichlorobenzyl)amino)pyrimidine-4-carboxylic acid
##STR00007##
[0097] The titled compound was synthesized with reference to the
method illustrated in Example 1, except that an appropriate amine
was used instead of [1,1'-biphenyl]-4-ylmethanamine in step 3 of
Example 1.
[0098] LC-MS m/z [M+H].sup.+=298
Example 4. Synthesis of
5-((furan-2-ylmethyl)amino)pyrimidine-4-carboxylic acid
##STR00008##
[0100] The titled compound was synthesized with reference to the
method illustrated in Example 1, except that an appropriate amine
was used instead of [1,1'-biphenyl]-4-ylmethanamine in step 3 of
Example 1.
[0101] LC-MS m/z [M+H].sup.+=220
Example 5. Synthesis of
5-(((3-methylthiophen-2-yl)methyl)amino)pyrimidine-4-carboxylic
acid
##STR00009##
[0103] The titled compound was synthesized with reference to the
method illustrated in Example 1, except that an appropriate amine
was used instead of [1,1'-biphenyl]-4-ylmethanamine in step 3 of
Example 1.
[0104] LC-MS m/z [M+H].sup.+=250
Example 6. Synthesis of
5-((4-fluorobenzyl)amino)pyrimidine-4-carboxylic acid
##STR00010##
[0106] The titled compound was synthesized with reference to the
method illustrated in Example 1, except that an appropriate amine
was used instead of [1,1'-biphenyl]-4-ylmethanamine in step 3 of
Example 1.
[0107] LC-MS m/z [M+H].sup.+=248
Example 7. Synthesis of
5-((3,5-bis(trifluoromethyl)benzyl)amino)pyrimidine-4-carboxylic
acid
##STR00011##
[0109] The titled compound was synthesized with reference to the
method illustrated in Example 1, except that an appropriate amine
was used instead of [1,1'-biphenyl]-4-ylmethanamine in step 3 of
Example 1.
[0110] LC-MS m/z [M+H].sup.+=366
Example 8. Synthesis of
5-((4-methoxybenzyl)amino)pyrimidine-4-carboxylic acid
##STR00012##
[0112] The titled compound was synthesized with reference to the
method illustrated in Example 1, except that an appropriate amine
was used instead of [1,1'-biphenyl]-4-ylmethanamine in step 3 of
Example 1.
[0113] LC-MS m/z [M+H].sup.+=260
Example 9. Synthesis of
5-((4-methylbenzyl)amino)pyrimidine-4-carboxylic acid
##STR00013##
[0115] The titled compound was synthesized with reference to the
method illustrated in Example 1, except that an appropriate amine
was used instead of [1,1'-biphenyl]-4-ylmethanamine in step 3 of
Example 1.
[0116] LC-MS m/z [M+H].sup.+=244
Example 10. Synthesis of
5-((3-fluorobenzyl)amino)pyrimidine-4-carboxylic acid
##STR00014##
[0118] The titled compound was synthesized with reference to the
method illustrated in Example 1, except that an appropriate amine
was used instead of [1,1'-biphenyl]-4-ylmethanamine in step 3 of
Example 1.
[0119] LC-MS m/z [M+H].sup.+=248
Example 11. Synthesis of
5-((2-fluorobenzyl)amino)pyrimidine-4-carboxylic acid
##STR00015##
[0121] The titled compound was synthesized with reference to the
method illustrated in Example 1, except that an appropriate amine
was used instead of [1,1'-biphenyl]-4-ylmethanamine in step 3 of
Example 1.
[0122] LC-MS m/z [M+H].sup.+=248
Example 12: Synthesis of
5-((1-propyl-1H-indazol-3-yl)amino)pyrimidine-4-carboxylic acid
##STR00016##
[0123] Step 1: Ethyl
5-((1-propyl-1H-indazol-3-yl)amino)pyrimidine-4-carboxylate
[0124] Ethyl 5-bromopyrimidine-4-carboxylate (35.0 mg, 0.15 mmol),
1-propyl-1H-indazol-3-amine (31.5 mg, 0.18 mmol), K.sub.2CO.sub.3
(62 mg, 0.45 mmol) and toluene (1 mL) were charged in a sealed tube
and the tube was then degassed. Xantphos (27 mg, 0.045 mmol) and
Pd.sub.2(dba).sub.3 (14 mg, 0.015 mmol) were added to the reaction
solution, followed by stirring at 110.degree. C. for 3 hours. After
completion of the reaction, the reaction solution was allowed to
cool to room temperature and filtered through a Celite pad using
ethyl acetate. The filtrate was concentrated under reduced pressure
and the obtained residue was purified by column chromatography
(silica, MPLC:EtOAc:n-Hexane 20:80 to 50:50) to obtain the titled
compound (29 mg, 59% yield) as a pale yellow solid.
[0125] LC-MS m/z [M+H].sup.+=326
Step 2: 5-((1-propyl-1H-indazol-3-yl)amino)pyrimidine-4-carboxylic
acid
[0126] Ethyl
5-((1-propyl-1H-indazol-3-yl)amino)pyrimidine-4-carboxylate (30 mg,
0.09 mmol) and LiCl (7.6 mg, 0.18 mmol) were added to a mix
solution of methanol (1 mL), THF (1 mL) and H.sub.2O (1 mL),
followed by stirring at room temperature for 30 minutes. After
completion of the reaction, the reaction solution was acidized with
an aqueous 1N HCl solution. The acidified solution was extracted
using a mix solution of chloroform/isopropanol (4:1). The collected
organic layer was dried over anhydrous magnesium sulfate and
filtered, and the solution was concentrated under reduced pressure
to obtain the titled compound (25.4 mg, 96%) as a pale yellow
solid.
[0127] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.37 (s, 1H),
9.90 (s, 1H), 8.80 (s, 1H), 7.68-7.65 (m, 2H), 7.47 (td, J=8.0, 2.4
Hz, 1H), 7.18 (td, J=8.0, 2.4 Hz, 1H), 4.34 (t, J=8.0 Hz, 2H), 1.89
(sextet, J=8.0 Hz, 2H), 0.88 (t, J=8.0 Hz, 3H)
Example 13. Synthesis of
5-((1-(2-(dimethylamino)ethyl)-1H-indazol-3-yl)amino)pyrimidine-4-carboxy-
lic acid
##STR00017##
[0129] The titled compound was synthesized with reference to the
method illustrated in Example 12.
[0130] LC-MS m/z [M+H].sup.+=327
Example 14.
5-((1-(3-benzamidopropyl)-1H-pyrazol-4-yl)amino)pyrimidine-4-carboxylic
acid
##STR00018##
[0131] Step 1: Tert-butyl
(3-(4-amino-1H-pyrazol-1-yl)propyl)carbamate
[0132] 4-nitro-1H-pyrazole (678.0 mg, 6.0 mmol),
3-(Boc-amino)propyl bromide (1712.3 mg, 7.22 mmol), K.sub.2CO.sub.3
(1161.0 mg, 8.4 mmol) and acetonitrile (MeCN; 20 mL) were charged
in a round-bottom flask, followed by stirring at 80.degree. C. for
12 hours. After completion of the reaction, the reaction solution
was allowed to cool to room temperature, was diluted with water and
then extracted using ethyl acetate. The collected organic layer was
dried over anhydrous magnesium sulfate and filtered, and the
solution was concentrated under reduced pressure to obtain the
titled compound (1,329.8 mg, 82% yield) as a pale yellow solid.
[0133] LC-MS m/z [M+H].sup.+=271
Step 2: Tert-butyl (3-(4-amino-1H-pyrazol-1-yl)propyl)carbamate
[0134] Tert-butyl (3-(4-nitro-1H-pyrazol-1-yl)propyl)carbamate
(1,300.0 mg, 4.81 mmol) was dissolved in ethanol (16 mL) and then
Pd/C (130.0 mg) was slowly added dropwise to the solution. The air
was removed by injecting hydrogen gas into the reaction solution
and the residue was stirred under a hydrogen gas atmosphere at room
temperature for 18 hours. After completion of reaction, the
reaction solution was washed with methanol and then filtered. The
collected filtrate was concentrated under reduced pressure to
obtain the titled compound (1,063.4 mg, 91% yield) as a pale yellow
solid.
[0135] LC-MS m/z [M+H].sup.+=241
Step 3: Ethyl
5-((1-(3-tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)amino)pyrimidi-
ne-4-carboxylate
[0136] Ethyl 5-bromopyrimidine-4-carboxylate (500 mg, 2.16 mmol),
tert-butyl (3-(4-amino-1H-pyrazol-1-yl)propyl)carbamate (780 mg,
3.25 mmol), K.sub.2CO.sub.3 (894 mg, 6.48 mmol) and toluene (20 mL)
were charged in a sealed tube and the tube was then degassed.
Xantphos (375 mg, 0.648 mmol) and Pd.sub.2(dba).sub.3 (434 mg, 0.22
mmol) were added to the reaction solution, followed by stirring at
110.degree. C. for 3 hours. After completion of the reaction, the
reaction solution was allowed to cool to room temperature filtered
through a Celite pad using ethyl acetate. The filtrate was
concentrated under reduced pressure and the obtained residue was
purified by column chromatography (silica, MPLC:DCM:MeOH=100:0 to
90:10) to obtain the titled compound (550 mg, 66% yield) as a pale
yellow solid.
[0137] LC-MS m/z [M+H].sup.+=391
Step 4: Ethyl
5-((1-(3-aminopropyl)-1H-pyrazol-4-yl)amino)pyrimidine-4-carboxylate
[0138]
5-((1-(3-tert-butoxycarbonyl)amino)propyl)-1H-pyrazol-4-yl)amino)py-
rimidine-4-carboxylate (356.8 mg, 0.91 mmol) was dissolved in
dichloromethane (16.4 mL), and a hydrochloric acid solution (4.0M
in 1,4-dioxane) was slowly added dropwise under stirring. When
solids were sufficiently precipitated, the solvent was distilled
under reduced pressure to obtain the titled compound (260.0 mg, 98%
yield) as a pale yellow solid.
[0139] LC-MS m/z [M+H].sup.+=291.
Step 5: Ethyl
5-((1-(3-benzamidopropyl)-1H-pyrazol-4-yl)amino)pyrimidine-4-carboxylate
[0140]
5-((1-(3-aminopropyl)-1H-pyrazol-4-yl)amino)pyrimidine-4-carboxylat-
e (250.0 mg, 0.86 mmol) was dissolved in dichloromethane (20 mL),
and benzoic acid (126 mg, 1.03 mmol),
1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxide hexafluorophosphate (HATU; 490.2 mg, 1.29 mmol),
hydroxybenzotriazole (HOBt; 197.4 mg, 1.29 mmol), and
N,N-diisopropylethylamine (DIPEA; 332.8 mg, 2.58 mmol) were slowly
added dropwise to the solution, followed by stirring at room
temperature for 12 hours. After completion of the reaction, the
reaction solution was diluted with water and the resulting solution
was extracted using dichloromethane. The collected organic layer
was dried over anhydrous magnesium sulfate and filtered, and the
solution was concentrated under reduced pressure. The obtained
residue was purified by column chromatography (silica,
MPLC:DCM:MeOH 100:0 to 90:10) to obtain the titled compound (273
mg, 81% yield).
[0141] LC-MS m/z [M+H].sup.+=395
Step 6:
5-((1-(3-benzamidopropyl)-1H-pyrazol-4-yl)amino)pyrimidine-4-carbo-
xylic acid
[0142] Ethyl
5-((1-(3-benzamidopropyl)-1H-pyrazol-4-yl)amino)pyrimidine-4-carboxylate
(273 mg, 0.69 mmol) and LiOH (138 mg, 3.45 mmol) were added to a
mix solution of methanol (3 mL), THF (3 mL) and H.sub.2O (3 mL),
followed by stirring at room temperature for 30 minutes. After
completion of the reaction, the reaction solution was acidified
with an aqueous 1N HCl solution. The acidified solution was
extracted using a mix solution of chloroform/isopropanol (4:1). The
collected organic layer was dried over anhydrous magnesium sulfate
and filtered, and the solution was concentrated under reduced
pressure to obtain the titled compound (127 mg, 50%)
[0143] .sup.1H NMR (400 MHz, DMSO-d) .delta. 8.74 (s, 1H). 8.56 (d,
J=5.6 Hz, 2H), 8.5 (t, J=5.2 Hz, 1H), 7.9 (s, 1H), 7.82 (d, J=7.2
Hz, 2H), 7.54 (s, 1H), 7.52-7.42 (m, 3H), 4.14 (t, J=6.8 Hz, 2H),
3.26 (q, J=6.8 Hz, 2H), 2.07-2.00 (m, 2H)
Example 15. Synthesis of
5-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidine-4-carboxylic acid
##STR00019##
[0145] The titled compound was synthesized with reference to the
method illustrated in Example 14.
[0146] LC-MS m/z [M+H].sup.+=220
Example 16. Synthesis of
5-((l-methyl-1H-pyrazol-4-yl)amino)pyrimidine-4-carboxylic acid
##STR00020##
[0148] The titled compound was synthesized with reference to the
method illustrated in Example 14.
[0149] LC-MS m/z [M+H].sup.+=220
Example 17. Synthesis of
5-(pyridazin-3-ylamino)pyrimidine-4-carboxylic acid
##STR00021##
[0151] The titled compound was synthesized with reference to the
method illustrated in Example 14.
[0152] LC-MS m/z [M+H].sup.+=218
Example 18. Synthesis of
5-(naphthalen-1-ylamino)pyrimidine-4-carboxylic acid
##STR00022##
[0154] The titled compound was synthesized with reference to the
method illustrated in Example 14.
[0155] LC-MS m/z [M+H].sup.+=266
Example 19. Synthesis of
5-((1-(3-(dimethylamino)propyl)-1H-pyrazol-4-yl)amino)pyrimidine-4-carbox-
ylic acid
##STR00023##
[0157] The titled compound was synthesized with reference to the
method illustrated in Example 14.
[0158] LC-MS m/z [M+H].sup.+=291.
Example 20. Synthesis of
5-((4-(4-ethylpiperazin-1-yl)phenyl)amino)pyrimidine-4-carboxylic
acid
##STR00024##
[0160] The titled compound was synthesized with reference to the
method illustrated in Example 14.
[0161] LC-MS m/z [M+H].sup.+=328
[0162] Meanwhile, the novel compound represented by Formula 1
according to the present invention can be prepared into a variety
of formulations depending on the purpose thereof.
[0163] Next, several formulation methods for incorporating the
compound represented by Formula 1 according to the present
invention as an active ingredient will be described in detail and
the present invention is not limited thereto.
Preparation Example
Preparation 1: Tablet (Direct Pressing)
[0164] 5.0 mg of an active ingredient was screened with a sieve,
was mixed with 14.1 mg of lactose, 0.8 mg of Crospovidone USNF and
0.1 mg of magnesium stearate, and then pressed to prepare a
tablet.
Preparation 2: Tablet (Wet Granulation)
[0165] 5.0 mg of an active ingredient was screened with a sieve,
and was mixed with 16.0 mg of lactose and 4.0 mg of starch. 0.3 mg
of polysorbate 80 was dissolved in pure water and an appropriate
amount of the resulting solution was added thereto, followed by
granulation. After drying, the resulting granules were screened,
and then mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg
of magnesium stearate. The granules were pressed to prepare a
tablet.
Preparation 3: Powder and Capsule
[0166] 5.0 mg of an active ingredient was screened with a sieve,
and then mixed with 14.8 mg of lactose, 10.0 mg of polyvinyl
pyrrolidone, and 0.2 mg of magnesium stearate. The resulting
mixture was charged into a hard No. 5 gelatin capsule using an
appropriate apparatus.
Preparation 4: Injection
[0167] 100 mg of an active ingredient was incorporated and 180 mg
of mannitol, 26 mg of Na.sub.2HPO.sub.4-12H.sub.2O and 2,974 mg of
distilled water were incorporated to prepare an injection.
[Test Example] Evaluation of Biological Activity
Test Example 1. Measurement of Inhibitory Activity Against Histone
Demethylase
[0168] Inhibitory activity against histone demethylase of the
compound of the present invention was evaluated. In vitro IC.sub.50
was calculated as inhibitory activity against KDM5A (lysine
demethylase 5A) and shown in the following Table 1.
TABLE-US-00001 TABLE 1 KDM5A Subject compound (.mu.M)
5-((1-propyl-1H-indazol-3-yl)amino)pyrimidine-4-carboxylic <3
acid (Example 12)
Test Example 2. Measurement of Growth Inhibitory Activity on
KDM5A-Overexpressed Cell Lines (MCF7)
[0169] The compound of the present invention was treated at a
single concentration with KDM5A-overexpressed breast cancer cells,
MCF7, and growth inhibitory activity was measured as an inhibition
proportion (%). Results are shown in the following Table 2.
TABLE-US-00002 TABLE 2 Growth inhibitory activity at Subject
compound 10 .mu.M
5-(([1,1'-biphenyl]-4-ylmethyl)amino)pyrimidine-4-carboxylic B acid
(Example 1) [Determination of inhibitory activity on cancer cell
proliferation] A: <40%, B: 40~80%, C: >80%
Test Example 3. Determination of Inhibitory Activity on Cancer Cell
Proliferation
[0170] The following test was conducted to identify whether the
compound of the present invention has inhibitory activity on cancer
cell proliferation.
[0171] The cancer cells herein used were lung cancer cell lines
(NCI-H1299, A549) and breast cancer cell lines (MDA-MB-231).
[0172] Specifically, the NCI-H1299 cells were large cell lung
carcinoma cell lines derived from human lung cancer tissues, and
the MDA-MB231 cells were cell lines derived from human breast
cancer tissues and obtained from the Korean cell line bank (KNCC,
Seoul university), which were used for tests after passage culture.
The NCI-H1299 and MDA-MB231 cell lines were cultured in a RPMI1640
medium supplemented with 10% FBS (fetal bovine serum), and were
washed with buffered saline (PBS, pH 7.4), when the cells were
proliferated on a plate at an affluence of 70 to 80%, and isolated
into single cells using a 0.05% trypsin-EDTA (welgene) solution,
and then passage-cultured at 1.times.10e6 cells/mL which were used
for the test. 100 .mu.L of NCI-H1299 and 100 .mu.L of MDA-MB231
were seeded on a 96-well plate at 2.times.10e4 cells/mL, and
5.times.10e4 cells/mL, respectively, stabilized in the presence of
CO.sub.2 for 12 hours or longer, and then treated at different
concentrations with the subject compound. After 72 hours,
absorbance was measured using a CellTiter-Glo.RTM. Luminescent Cell
Viability Assay (Promega) and an Envision 2103 multilabel reader
(PerkinElmer). At this time, cells treated only with
dimethylsulfoxide (DMSO) were used as the control group and
relative viability (%) was calculated, based on 100% of the control
group. GI.sub.50 was obtained using Graph PRISM 6 software.
[0173] The inhibitory activity on cancer cell proliferation
measured by the method is shown in the following Tables 3, 4 and
5.
TABLE-US-00003 TABLE 3 NCI-H1299 inhibitory Subject compound
activity 5-((3-fluorobenzyl)amino)pyrimidine-4-carboxylic acid A
(Example 10) [Determination of inhibitory activity on cancer cell
proliferation] A: GI.sub.50 < 10 .mu.M, B: 10 .mu.M <
GI.sub.50 < 100 .mu.M, C: GI.sub.50 > 100 .mu.M
TABLE-US-00004 TABLE 4 A549 inhibitory Subject compound activity
5-((3,4-dichlorobenzyl)amino)pyrimidine-4-carboxylic B acid
(Example 3)
5-((1-propyl-1H-indazol-3-yl)amino)pyrimidine-4-carboxylic B acid
(Example 12) [Determination of inhibitory activity on cancer cell
proliferation] A: GI.sub.50 < 10 .mu.M, B: 10 .mu.M <
GI.sub.50 < 100 .mu.M, C: GI.sub.50 > 100 .mu.M
TABLE-US-00005 TABLE 5 Subject compound MDA-MB-231
5-((3,4-dichlorobenzyl)amino)pyrimidine-4-carboxylic B acid
(Example 3) 5-((4-fluorobenzyl)amino)pyrimidine-4-carboxylic B acid
(Example 6) 5-((3,5-bis(trifluoromethyl)benzyl)amino)pyrimidine-4-
B carboxylic acid (Example 7)
5-((4-methylbenzyl)amino)pyrimidine-4-carboxylic B acid (Example 9)
5-((1-propyl-1H-indazol-3-yl)amino)pyrimidine-4- B carboxylic acid
(Example 12) [Determination of inhibitory activity on cancer cell
proliferation] A: GI.sub.50 < 10 .mu.M, B: 10 .mu.M <
GI.sub.50 < 100 .mu.M, C: GI.sub.50 > 100 .mu.M
* * * * *